Clinical Context

Juvenile idiopathic arthritis (JIA) is a chronic, immune-mediated inflammatory disease with monophasic to chronic, often fluctuating, unpredictable disease course. Clarifying classification criteria is essential for clinical trials and epidemiologic studies.

A recent study published in Arthritis Care & Research followed children diagnosed with JIA for 18 years. The study highlights the International League of Associations for Rheumatology (ILAR) consensus-based classification criteria as an imperfect method to categorize patients with JIA.

Study Synopsis and Perspective

Mia Glerup, MD, PhD, from the Department of Pediatrics at Aarhus University Hospital in Aarhus, Denmark, and colleagues prospectively analyzed 373 patients from Denmark, Norway, Sweden, and Finland with new-onset JIA between 1997 and 2000 and evaluated them at baseline, 8 years, and 18 years. At each visit, the researchers collected data on demographics, disease activity, ILAR category, treatment, and blood samples.

Patients in the cohort were mostly girls (66.7%) with a median age of 5.9 years at onset.34.8% of patients were antinuclear antibody (ANA) positive and 21.6% were HLA-B27 positive. The most common JIA categories at baseline were persistent oligoarthritis (53.9%), polyarticular rheumatoid factor (RF) negative (21.1%), and undifferentiated arthritis (10.2%).

Dr Glerup and colleagues found that the proportion of patients not receiving DMARDs declined from 73.2% at baseline to 59.7% at 8 years, and then rose again to 70.0% at 18 years (risk ratio, 1.3; P=.003). The group of 103 patients who used conventional DMARDs (cDMARDs) either as monotherapy or in combination with a biologic DMARD (bDMARD) at 8 years dwindled to 44 (42.7%) at 18 years (RR, 0.4; P<.001), whereas 32 (61.5%) of 52 patients using bDMARDs at 8 years were still receiving them at 18 years (RR, 0.6; P =.02). Across the whole study, 14.7% of patients never received any JIA treatment, and 33 (38.8%) of 85 patients receiving continuous DMARDs developed uveitis during the study period.

Overall, 62.7% of patients received DMARDs at least once, including 89.7% with polyarticular RF negative, 77.3% with oligoarticular extended, 76.9% with systemic, 75.7% with juvenile enthesitis-related arthritis, 66.7% with polyarticular RF-positive, 65.2% with juvenile psoriatic arthritis, 58.9% with undifferentiated JIA, and 27.6% of patients with persistent oligoarticular disease.

The median number of active joints dropped from 3 (range, 1-30) at baseline to 0 at 8 years (range, 0-13), whereas the median cumulative number of affected joints was rose from 3 at baseline (range, 1-30) to 6 at 8 years (range, 1-41). At last follow-up, the median number of active joints was 0 (range, 0-5) and median cumulative number of affected joints was 7 (range, 1-47). The percentage of patients in remission barely changed from 52% at 8 years to 51% at 18.

Some patients also changed ILAR categories during the study period, with 7% shifting between baseline and 8 years and 11% shifting between 8-year and 18-year follow-up. Compared with baseline, by the 18-year follow-up point there was a significant decrease in the number of patients categorized as oligoarticular (230 vs 197 patients; P=.02), a significant increase in patients in the psoriatic ILAR category (8 vs 28 patients; P<.001), and a nonsignificant increase in the number of patients in the undifferentiated category (45 vs 63 patients; P=.06).

"Almost half of the changes in the distribution between the ILAR categories were caused by updated information on heredity in a first degree relative obtained at the follow-up visits," Dr Glerup and colleagues write.

The results of the long-term study show that patients are "likely to remain in remission, with the converse also evident, as patients still with evidence of disease activity at 8 years after disease onset were more likely to have refractory disease," Dr Wahezi said.

Commenting on the study's findings, Lisa F. Imundo, MD, director of adolescent rheumatology at Columbia University Medical Center in New York City, said they are "great news to be able to give parents of young kids with arthritis." However, she questioned whether the results are generalizable to populations of patients "who are in the worst prognostic group."

Although the study is valuable for its long-term follow-up, there is also a question of generalizability across a more diverse ethnic and racial group. The authors do not elaborate on the racial breakdown of their patients, Dr Imundo said.

However, long-term registries evaluating JIA in more diverse populations, such as the Childhood Arthritis and Rheumatology Research Alliance (CARRA) registry, could confirm these results, said Dr Hausmann, who is a registry informatics associate with CARRA and was not associated with the research.

Long-Term Management of JIA

In an accompanying editorial, Jaime Guzman, MD, and Ross E. Petty, MD, PhD, from British Columbia Children's Hospital and the University of British Columbia, Vancouver, Canada, said that a rheumatologist's interpretation of the study would be tied to what they learned about children with arthritis in medical school.^[2] They would see the glass as "half full" if children who achieved remission stayed in remission if they learned that a child might end up outgrowing JIA but potentially develop lifelong disability, whereas others may focus on the outcome of approximately half of patients not achieving remission.

"I think this study and many other studies have shown that that's actually not the case--that in fact, it may be a majority of kids continue having active disease even through adulthood" Dr Hausmann said.

Education on the part of the patient, their parents, and their clinician on the expected trajectory of the disease is critical so that children can continue their own care as they transition to adulthood, Dr Hausmann explained. "The earlier the kids develop the skills to discuss their medicines, their side effects, the better they'll be able to transition to adult medicine," he said.

For the patients who go into remission and stay in remission, the message is also important. "To have the reassurance that a lot of those kids won't be having active joint symptoms or need to be on medication, that's a huge positive message that can get out there," Dr Imundo said.

Time to Move on From ILAR Classification?

Another takeaway from the study was how patients' ILAR classification changed across the 18-year follow-up. The ILAR classification considers a patient's history when categorizing JIA types but also includes factors such as immediate family history. This system of assessing JIA has been criticized, and there are initiatives to create a new JIA classification system to replace it.^[6,7]

"The ILAR criteria were designed to classify patients 6 months after disease onset in an attempt to find some commonality in clinical phenotypes, prognosis, and suggested management," Dr Wahezi said. "While there continues to be debate as to whether we can improve our classification of JIA patients, it is not surprising that phenotypes may evolve over time as new clinical features develop.”

Although the percentage of patients who switched ILAR classifications during the study period was "much higher" than she thought, Dr Imundo said it was the reasons provided in the study that seemed odd to her. "The classification scheme relies on your family history, like someone else in your family now has psoriasis, so your arthritis classification changes," she explained.

"We want to head toward a much more unified classification scheme--a simpler one. We now understand that some of the diseases that we see in pediatrics are really the equivalent or same disease in adults," she said.

"Most of the pediatric categories of JIA have distinct adult correlates," Dr Hausmann agreed. RF-positive polyarthritis in children and rheumatoid arthritis in adults are correlated, as are systemic JIA and adult-onset Still's disease.

Some pediatric rheumatologists accept that the classification system is flawed, but not all concur with the degree to which these problems affect patient care. "While the ILAR classification criteria may be subject to criticism, it does provide general context and prognostic implications for patients and families," Dr Wahezi said.

"The medicines certainly are very similar across the JIA categories, so the implications are not as broad" when classification changes, Dr Hausmann said. "But it certainly shows that there are things that we still don't know. I think classification is actually pretty important because it might give you a sense of how persistent the disease will be."

Dr Imundo said that the ILAR classification's "time is limited." "These categories are so imperfect, and the patients are changing. I feel like that says to me, let's find something that's more predictive that really helps us a little better than what we have now," she said.

The study had no specific funding. The authors of the study and the editorial have disclosed no relevant financial relationships. Dr Hausmann reports receiving salary support from CARRA. Dr Imundo and Dr Wahezi have disclosed no relevant financial relationships.

Arthritis Care Res. Published online January 10, 2022.

Clinical Implications

• JIA remission rate did not increase even though significantly more patients were off medication at 18 years vs 8 years after onset.
• Distribution of patients in ILAR categories continued to change significantly throughout the 18-year study, mandating more predictive criteria.
• Implications for the Health Care Team: Patients, families, and clinicians need education regarding expected disease trajectory.

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